Interpretive Handbook

Test
9030 :
Antithrombin Activity, Plasma

Antithrombin is a member of the serine protease inhibitor (serpin) superfamily. It is the principal plasma anticoagulant serpin mediating inactivation of serine protease procoagulant enzymes, chiefly thrombin and coagulation factors Xa and IXa.(1) Heparin and certain other naturally occurring glycosaminoglycans markedly enhance antithrombin's anticoagulant activity (approximately 1,000-fold) by providing a template to catalyze formation of covalently bonded, inactive complexes of serine protease and antithrombin that are subsequently cleared from circulation. Antithrombin is the mediator of heparin's anticoagulant activity.

The antithrombin gene on chromosome 1 encodes a glycoprotein of approximately 58,000 molecular weight that is synthesized in the liver and is present in a relatively high plasma concentration (approximately 2.3 umol/L). The biological half-life of antithrombin is 2 to 3 days.

Hereditary antithrombin deficiency, a relatively rare autosomal dominant disorder, produces a thrombotic diathesis (thrombophilia). Individuals with hereditary antithrombin deficiency are usually heterozygous with plasma antithrombin activity results of approximately 40% to 70%. These patients primarily manifest with venous thromboembolism (deep vein thrombosis [DVT] and pulmonary embolism [PE]) with the potential of development as early as adolescence or younger adulthood. More than 100 different mutations have been identified throughout the gene producing either the more common type I defects (low antithrombin activity and antigen) or the rarer type II defects (dysfunctional protein with low activity and normal antigen).(2) Homozygous antithrombin deficiency appears to be incompatible with life.

The incidence of hereditary antithrombin deficiency is approximately 1:2,000 to 1:3,000 in general populations, although minor deficiency (antithrombin activity = 70%-75%) may be more frequent (approximately 1:350-650). In populations with venous thrombophilia, approximately 1% to 2% have antithrombin deficiency. Among the recognized hereditary thrombophilic disorders (including deficiencies of proteins C and S, as well as activated protein C [APC]-resistance [factor V Leiden mutation]), antithrombin deficiency may have the highest phenotypic penetrance (greater risk of venous thromboembolism). Arterial thrombosis (eg, stroke, myocardial infarction) has occasionally been reported in association with hereditary antithrombin deficiency.

Hereditary deficiency of antithrombin activity can also occur because of defective glycosylation of this protein in individuals with carbohydrate-deficient glycoprotein syndromes (CDGS).(3) Antithrombin activity assessment may be useful as an adjunct in the diagnosis and management of CDGS.

Acquired deficiency of antithrombin is much more common than hereditary deficiency. Acquired deficiency can occur due to:

In general, the clinical implications (thrombotic risk) of antithrombin deficiency in these disorders are not well defined, although antithrombin replacement in severe DIC/IFC is being evaluated.(4) Assay of antithrombin activity may be of diagnostic or prognostic value in some acquired deficiency states.

Antithrombin deficiencies due to inherited causes are much less common than those due to acquired causes (see Clinical Information). Diagnosis or hereditary deficiency requires clinical correlation, with the prospect of repeat testing (including antithrombin antigen assay) and family studies (with appropriate counseling). DNA-based diagnostic testing may be helpful, but is not readily available.

Antithrombin deficiency, acquired or congenital, may contribute to the phenomenon of "heparin therapy resistance" (requirement of larger heparin doses than expected for achievement of therapeutic anticoagulation responses). However, it may more often have other pathophysiology, such as "acute-phase" elevation of coagulation factor VIII or plasma heparin-binding proteins.